Pancreatic ductal
adenocarcinoma (PDA) is an aggressive
malignancy with one of the worst outcomes among all
cancers. PDA often recurs after initial treatment to result in patient death despite the use of
chemotherapy or
radiation therapy. PDA contains a subset of tumor-initiating cells capable of extensive self-renewal known as cancer stem cells (CSC), which may contribute to therapeutic resistance and
metastasis. At present, conventional
chemotherapy and
radiotherapy are largely ineffective in depleting CSC pool, suggesting the need for novel
therapies that specifically target the
cancer-sustaining stem cells for
tumor eradication and to improve the poor prognosis of PDA patients. In this study, we report that
death receptor 5 (DR5) is enriched in pancreatic CSCs compared with the bulk of the
tumor cells. Treating a collection of freshly generated patient-derived PDA xenografts with
gemcitabine, the first-line chemotherapeutic agent for PDA, is initially effective in reducing
tumor size, but largely ineffective in diminishing the CSC populations, and eventually culminated in
tumor relapse. However, a combination of
tigatuzumab, a fully humanized DR5 agonist
monoclonal antibody, with
gemcitabine proved to be more efficacious by providing a double hit to kill both CSCs and bulk
tumor cells. The combination
therapy produced remarkable reduction in pancreatic CSCs,
tumor remissions, and significant improvements in time to
tumor progression in a model that is considered more difficult to treat. These data provide the rationale to explore the DR5-directed
therapies in combination with
chemotherapy as a therapeutic option to improve the current standard of care for
pancreatic cancer patients.